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  • Review Article Role of Viral miRNAs and Epigenetic Modifications in Epstein-Barr Virus-Associated Gastric Carcinogenesis

    Aldo Giudice,1 Giovanni D’Arena,2 Anna Crispo,1 Mario Felice Tecce,3

    Flavia Nocerino,1 Maria Grimaldi,1 Emanuela Rotondo,1 Anna Maria D’Ursi,3

    Mario Scrima,3 Massimiliano Galdiero,4 Gennaro Ciliberto,5 Mario Capunzo,6

    Gianluigi Franci,4 Antonio Barbieri,7 Sabrina Bimonte,8 and Maurizio Montella1

    1Epidemiology Unit, National Cancer Institute of Naples “G. Pascale Foundation”, IRCCS, 80131 Naples, Italy 2Department of Onco-Hematology, IRCCS, Cancer Referral Center of Basilicata, 85028 Rionero in Vulture, Italy 3Department of Pharmacy, University of Salerno, Fisciano, 84084 Salerno, Italy 4Department of Experimental Medicine II, University of Naples, 81055 Naples, Italy 5Scientific Direction, National Cancer Institute “G. Pascale Foundation”, IRCCS, 80131 Naples, Italy 6Department of Medicine and Surgery, University of Salerno, Baronissi, 84081 Salerno, Italy 7Animal Facility Unit, National Cancer Institute of Naples “G. Pascale Foundation”, IRCCS, 80131 Naples, Italy 8Division of Abdominal Surgical Oncology, Hepatobiliary Unit, National Cancer Institute “G. Pascale Foundation”, IRCCS, 80131 Naples, Italy

    Correspondence should be addressed to Aldo Giudice;

    Received 23 October 2015; Revised 12 January 2016; Accepted 14 January 2016

    Academic Editor: Denis Delic

    Copyright © 2016 Aldo Giudice et al. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

    MicroRNAs are short (21–23 nucleotides), noncoding RNAs that typically silence posttranscriptional gene expression through interaction with target messenger RNAs. Currently, miRNAs have been identified in almost all studied multicellular eukaryotes in the plant and animal kingdoms. Additionally, recent studies reported that miRNAs can also be encoded by certain single-cell eukaryotes and by viruses.The vastmajority of viralmiRNAs are encoded by the herpesviruses family.TheseDNAviruses including Epstein-Barr virus encode their ownmiRNAs and/ormanipulate the expression of cellularmiRNAs to facilitate respective infection cycles. Modulation of the control pathways of miRNAs expression is often involved in the promotion of tumorigenesis through a specific cascade of transduction signals. Notably, latent infection with Epstein-Barr virus is considered liable of causing several types of malignancies, including the majority of gastric carcinoma cases detected worldwide. In this review, we describe the role of the Epstein-Barr virus in gastric carcinogenesis, summarizing the functions of the Epstein-Barr virus-encoded viral proteins and related epigenetic alterations as well as the roles of Epstein-Barr virus-encoded and virally modulated cellular miRNAs.

    1. Introduction

    TheEpstein-Barr virus (EBV) was the first discovered human tumor-causing virus considered as the etiologic agent of Burkitt’s lymphoma (BL), an unusual African pediatric lym- phoma [1].

    Specifically, EBV is ubiquitous member of the human gamma-herpesvirus family that causes mononucleosis dur- ing acute and lytic infection and also establishes a persis- tent and latent infection in more than 90% of the human

    population. EBV latent infection has been demonstrated to be involved inmultiple types of cancer that primarily develop in lymphocytes and epithelial cells. These include malignant tumors that develop in the immunocompromised conditions such as AIDS-associated lymphomas and posttransplant lymphoproliferative disease [2, 3] and also several human cancers that develop in the immunocompetent patients such as BL, Hodgkin’s lymphoma, B-cell and T-cell lymphomas, epithelial nasopharyngeal carcinoma (NPC), and some forms of gastric carcinomas [4–6]. Gastric cancer is the fourth

    Hindawi Publishing Corporation Oxidative Medicine and Cellular Longevity Volume 2016, Article ID 6021934, 11 pages

  • 2 Oxidative Medicine and Cellular Longevity

    Gastric carcinoma and other malignancies


    Viral mRNA degradation or

    translation inhibition

    Degradation Degradation Translation Translation

    Host cell mRNA degradation or

    translation inhibition

    Aberrant DNA methylation and inactivation of tumor suppressor


    Host cell genome

    Increase persistent latent infection in the

    host cells

    Reduce host immune


    Regulate cell signaling, cell division, and


    Risc Viral miRNAs

    Viral proteins (LMP2A)

    Viral DNA


    Figure 1: Graphical representation of possible mechanisms by which viral miRNAs and viral proteins might contribute to EBV-associated gastric carcinogenesis. This model indicates that EBV-encoded miRNAs (e.g., BART miRNAs and BHRF-1 miRNAs) target viral genes to mediate immune evasion or maintenance of latency, whereas some viral proteins (e.g., LMP2A) promote aberrant host DNA methylation and subsequent inactivation of tumor suppressor genes via DNA methyltransferases (DNMTs) induction. In addition, these viral miRNAs incorporated into RISC complex can also interact directly with specific host genes involved in immune surveillance, cell proliferation, and apoptosis, playing a crucial role in the aetiology of diverse diseases including EBVaGC.

    most common cancer in the world and the second leading cause of cancer-related death. Globally, gastric cancer poses a significant public health burden, both economically and socially [7, 8]. Risk factors of gastric cancer aremultifactorial; hence genes, diet, age, and chronic inflammation need to be evaluated in connection with infectious agents (EBV, Helicobacter pylori) and environmental factors (e.g., alcohol and smoking) [8]. Notably, EBV-associated gastric carcinoma (EBVaGC) represents almost 10% of all gastric carcinoma cases and expresses restricted EBV latent genes (Latency I) [4, 9]. In recent years, it has become increasingly evident that EBV may contribute to gastric carcinogenesis through the expression of viral proteins and microRNAs (miRNAs) [10] (Figure 1). A growing body of scientific evidence also suggests that, in addition to genetic alterations, epigenetic alterations, including aberrant DNA methylation of CpG islands and posttranslational modifications of histones, are involved in the development and progression of EBVaGC [10, 11]. This review briefly summarizes remarkable advancements in our understanding of the functions and mechanisms of action of herpesviral miRNAs in gastric carcinoma in recent years. In particular it discusses how the expression of viral proteins and epigenetic alterations contribute to EBVaGC and the roles of EBV-encoded and virally modulated cellular miRNAs in

    the respective viral life cycles and in EBV-associated gastric carcinoma.

    2. Biogenesis of EBV-Encoded miRNAs

    The generation of viral miRNA and selection of targets are totally dependent on the host molecular miRNA apparatus involved in the maturation and silencing. Most viruses utilize a strategy similar to that of the host cell to produce the viral pri-miRNAs by using the host RNA polymerase II (RNAP II) [12, 13]. Exceptionally, certain viral miRNAs (such as those from mouse 𝛾-herpesvirus 68, MHV68) are produced from tRNA-like genes transcribed by host RNA polymerase III (RNAP III) and processed Drosha independently by host tRNase Z [14]. Aminority of viruses from the herpesvirus and retrovirus families also utilize noncanonical pathways other than “tRNA-like” to generate pre-miRNAmolecules [15–22]. For instance, herpesvirus saimiri (HVS), an oncogenic 𝛾- herpesvirus that infects NewWorldmonkeys, expresses small nuclear RNAs (snRNAs) of the Sm-class called HSURs which are processed by the integrator complex to produce viral pre-miRNAs. Subsequently, both the MHV68 and HVS pre- miRNAs are processed by Dicer to generate miRNAs [23]. Additionally, some retroviruses such as foamy viruses (FVs)

  • Oxidative Medicine and Cellular Longevity 3

    and bovine leukemia virus (BLV) are able to express pri- miRNAs via RNAP III [18, 19, 21]. While some retroviral pri- miRNAs are processed by Drosha in the frame of RNAP III transcripts, some others may be directly processed by Dicer bypassing Drosha processing. Production of retroviral miR- NAswithout having recourse to Drosha-mediated cleavage of the RNA genome intermediate has been found to represent an important biogenesis strategy that may eventually take an active part in reducing overall viral fitness [18, 19, 21]. In brief, viral miRNA biogenesis initiates in the nucleus, where after transcription by host RNA polymerase II the microprocessor complex which contains the host RNase III endonuclease Drosha and its interaction partner DGCR8 (also known as Pasha in Drosophila) [24] cleaves pri-miRNA hairpin structure to pre-miRNAs. The vast majority of pri- miRNAs contain approximately 80 nucleotide hairpin sec- ondary structures that can be intronic or exonic. Approxi- mately 60 pre-miRNA nucleotides are liberated and rapidly exported from the nucleus to the cytoplasm by exportin- 5/Ran GTPase pathway. Once in the cytoplasm, they are further processed by a second host RNase III endonuclease, Dicer, into a short double-stranded (ds) RNA or RNAduplex. The strand guide of these mature miRNAs of approximately 22 nucleotides is then incorporated into a protein complex known as the RNA-induced silencing complex (RISC), while the other strand called the passenger is rapidly